Abstract 4043: KSHN001034: An intramuscular prodrug of fulvestrant to treat estrogen-receptor (ER) positive advanced metastatic breast cancer
Authors: Heta Pandya, Ganesh Sangle, Vishal Unadkat, Vishal Goswami, Parva Purohit, Chirag Mehta, Sonam Sinha, Ketan Variya
Journal: Cancer Research (2022)

Abstract Purpose: Breast cancer (BC) remains a considerable health concern, with over 75% of total cases accounting for ER+ BC. Fulvestrant, a selective estrogen receptor degrader (SERD), is the primary drug of choice for treating advanced metastatic ER+, BC. Currently, Faslodex® (500 mg) is given as an intramuscular (IM) depot that achieves the steady-state plasma concentration of 24-28 ng/mL of fulvestrant from day 28 onwards. Additionally, clinical studies suggest that current Faslodex® (500 mg) achieves insufficient blockade of ERα receptor plausibly due to suboptimal physicochemical and pharmacokinetic (PK) properties. Hence, achieving higher fulvestrant plasma concentrations is a significant unmet need to improve efficacy and inhibit the development of drug resistance. To overcome these issues, we modified the physicochemical properties of the fulvestrant to enhance its solubility by developing a prodrug, KSHN001034, with the potential to deliver higher fulvestrant plasma exposures. Methods: KSHN001034 was evaluated for its physicochemical and ADME properties. Thermodynamic solubility and liver microsomal stability were performed. KSHN001034 was formulated as 100 mg/mL compared with Faslodex (50 mg/mL). Single-dose PK studies were performed using KSHN001034 in Sprague Dawley (SD) rats and Beagle Dogs post-IM administration for 7 and 14 days, respectively. The uterotrophic activity was investigated by determining changes in uterine weight in juvenile female SD rats for KSHN001034 (10 mg/kg, IP) and fulvestrant (25 mg/kg, SC). The ERα expression was also evaluated in rat uterus tissue via a simple western assay. Results: A remarkable improvement (~1100 fold) was achieved for KSHN001034 in aqueous solubility (1.112 mg/mL) vs. fulvestrant (&amp;lt;1 µg/mL). Significant improvement was observed in metabolic stability vs. fulvestrant. KSHN001034 showed significant improvement in PK exposure of fulvestrant upon IM administration in rats and dogs with higher AUC and Cmax compared to that of Faslodex. Relative bioavailability of fulvestrant post-KSHN001034 treatment was found to be &amp;gt;6-fold in rats and ~2.5 fold in dogs compared to Faslodex. Treatment of KSHN001034 antagonized estradiol (E2)-mediated uterine stimulation, exhibiting significant inhibition (85%) of uterotrophic activity vs. fulvestrant (73%). KSHN001034 reduced E2-induced uterus weight, supporting efficacy due to released fulvestrant as it is a true SERD. Additionally, KSHN001034 significantly inhibited the E2-induced ERα expression in rat uterus. Conclusions: Overall, KSHN001034 indicates the potential to deliver higher fulvestrant concentrations that would effectively block the ERα receptor resulting in improved efficacy and minimal emergence of resistance. Further, enhanced solubility and reduced injection volume would result in better patient compliance. Citation Format: Heta Pandya, Ganesh Sangle, Vishal Unadkat, Vishal Goswami, Parva Purohit, Chirag Mehta, Sonam Sinha, Ketan Variya. KSHN001034: An intramuscular prodrug of fulvestrant to treat estrogen-receptor (ER) positive advanced metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4043.